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The Human Genome Project: an adventure in research that has delivered great benefit

By Jill Trewhella

30 May 2013

A few weeks ago I piece that I wrote appeared in a heavily edited version in"The Conversation". The editors did a great job in turning what I wrote into a good piece of journalism, but when I compared where my piece started and where it ended, I feel that the essential message of my story was lost in translation. My story was about how research advances in unexpected ways when the environment creates opportunities for inter-disciplinary research and it had more technical detail. So while my original story may be less riveting, I am posting it for those who might be interested in the more technical aspects of how the human genome project got its start!

The Human Genome Project was a game changer as the first large-scale coordinated effort in the history of biological research. It emerged toward the end of the 20th century which had been largely the century for physics, stimulated in large part by big projects undertaken to win a world war such as the Manhattan Project led from Los Alamos New Mexico, and the Rad Lab at the Massachusetts Institute of Technology.

Among the initial proponents of the Genome Project were, in a sense, scientific descendents of the Manhattan Project; those in the US Department of Energy's (DOE's) Office of Health and Environmental Research (OHER), led for a period in the 1980's by Charles DeLisi. DeLisi had come to the DOE from the National Institutes of Health (NIH) and came to the view that understanding human susceptibility to environmental energy emissions could benefit from knowledge to the genome and genetic mutations linked to such susceptibility.

At the time, DOE's National Laboratory Gene Library Project (NLGLP) was providing chromosome specific DNA libraries to researchers all over the world, a capability developed from Los Alamos researchers pioneering work in flow cytometry. Los Alamos was also home to the gene sequence data base GenBank that would eventually move to the National Library of Medicine. Both the NLGLP and Genbank were critically important precursors leading to the Genome Project.

DeLisi asked the then head of Life Science at Los Alamos, Mark Bitensky, to convened one of the landmark early workshops leading up to the project that was held in Santa Fe, New Mexico in 1986. From this workshop, the DOE OHER Advisory Committee recommended a major project to map the entire genome and identify all of the gene sequences.

At the same time, there were a number of voices that independently were thinking this was a good idea, however there was considerable debate as to whether the technology to sequence the 3.3b base pairs that make up the human genome was ready to take on the task of whole genome sequencing. There were opposing voices in the science community who felt that biology was the realm of the individual researcher and that such a large project would consume all of the research funding and leave the entrepreneurial, innovative research leader starved for resources.

In a climate of controversy but also of big vision, the first funding ($13m) for the effort flowed from the DOE, and in 1990 the Human Genome Project was established formally as a joint project funded by the US National Institutes of Health and the DOE with initial estimates were that the project would cost $USD3b and take 15 years. The work was ultimately completed at numerous universities and research centers throughout the United States, and also in the United Kingdom (with funds from the Wellcome Trust) as well as sites in France, Germany, Japan and China.

The project would be completed ahead of schedule, in large part a demonstration of the importance of competition and open access to data in research. The public project was moving ahead, when Crag Ventor and his company Celera Genomics entered the frame in 1998 in direct competition with the public project. Ventor's innovation was to use "whole genome shot-gun sequencing," previously used in sequencing smaller bacterial genome sequences but never applied to something as large as the human genome.

Rather than walking the chromosome sequences piece by piece, Ventor's team would break the sequence into smaller parts and sequence the ends and reassemble the sequence (computationally) by lining up the overlapping sequenced segments. The competition was fierce and there was skepticism that the Ventor approach would lead to an accurate result. There also was great public controversy over Ventor's proposal to seek patents on 200-300 human genes, that was ended when President Clinton announced that the genome sequence should be made freely available to all researchers and could not be patented (March, 2000). This statement resulted in a $50n loss in the biotechnology industry and Celera's stock price plummeted.

The end result was that public and private projects jointly published the draft human genome sequence in papers in Nature in June of 2000, and the event was announced jointly by President Bill Clinton and Prime Minister Tony Blair. On April, 2003, the anniversary of Watson and Crick's publication in Nature of the structure of DNA and their prediction of the chemical basis for DNA replication, the international public project announced an essentially finished version of the human genome sequence.

The human genome project has changed science. It has contributed to making biology the science of the 21st century as physics was the science of the 20th century. It has driven advances in our understanding of biology at the cellular and molecular levels and provided new tool for medicine. It has led to routine genetic testing for many diseases including breast cancer and cystic fibrosis. Our understanding of the causes of diseases such as cancer and Alzheimer's disease is being informed by our knowledge of the human genome. The extraordinary advances in sequencing technology that emerged from the project has led to sequence data bases critically important for public health and biosecurity; such as the HIV, Influenza, and pathogen sequence data bases.

Having been recruited to Los Alamos in 1984 by Mark Bitensky, ultimately to lead Bioscience Division there from 1999-2004, I was witness to this historic and exciting time in the history of biological research. I experienced the richness of the multidisciplinary environment that was essential to the genesis and development of the Human Genome Project. The sequencing team in my Division was responsible for producing the draft and finished sequences of chromosome 16, as well as contributing to finishing other chromosomes. We felt the terror of knowing that the draft sequence had to be completed by a specific date because a prime minister and a president wanted to make an announcement on a particular date, and then we were held ransom to a later date associated with the publications of an iconic scientific discovery 50 years earlier. It is a time I remember well and cherish greatly.